Early exposure to a methyl donor supplemented diet and the development of repetitive motor behavior in a mouse model.

Motor behaviors that are repetitive and exhibit little variability in form are common in neurodevelopmental disorders (e.g., autism spectrum disorder). C58 mice exhibit persistent, high levels of repetitive motor behavior when reared in restricted, but not enriched, environments implicating epigenetic mechanisms (e.g., DNA methylation). We sought to determine if alteration of DNA methylation played a role in the development of repetitive behavior in C58 mice. Thus, we tested the hypothesis that early exposure (in utero and preweaning) to a methyl donor supplemented diet would alter the developmental trajectory of repetitive behavior. Such dietary exposure resulted in significant attenuation of repetitive motor behavior development, persisting through early adulthood. This was despite mice being housed in standard cages and maintained on a standard diet, postweaning. Early exposure to methyl donor supplementation not only affected the frequency of repetitive behavior but also its temporal structure, resulting in more variable patterns of repetitive behavior. Early exposure to the diet was also shown to induce long-lasting increases in DNA methylation in brain tissue of female mice. The role for alterations in DNA methylation in this model may be one mechanism accounting for the robust effects of the environment on the development of repetitive behavior.

Targeting Dopamine D2, Adenosine A2A, and Glutamate mGlu5 Receptors to Reduce Repetitive Behaviors in Deer Mice.

Repetitive behaviors are seemingly purposeless patterns of behavior that vary little in form and are characteristic of many neurodevelopmental, psychiatric, and neurologic disorders. Our work has identified an association between hypofunctioning of the indirect basal ganglia pathway and the expression of repetitive behavior in the deer mouse model. In this study, we targeted indirect pathway cells of the striatum with single drugs and drug combinations that bind to dopamine D2, adenosine A2A, and glutamate mGlu5 receptors. These receptors function both individually and as receptor heteromers. We found that only the triple drug cocktail (L-741,626+CGS21680+CDPPB) that was designed to increase striatal indirect basal ganglia pathway cell function reduced repetitive behavior in adult male deer mice. No single drug or double drug combinations were effective at selectively reducing repetitive behavior. We found this triple drug cocktail reduced repetitive behavior in both short-acting and long-acting formulations and was effective throughout 7 days of daily administration. Conversely, another triple drug cocktail (quinpirole+SCH58261+MTEP) that was designed to further reduce striatal indirect basal ganglia pathway cell function caused a significant increase in repetitive behavior. Significant and behaviorally selective effects on repetitive behavior were only achieved with the triple drug cocktails that included doses of L-741,626 and quinpirole that have off-target effects (e.g., dopamine D3 receptors). These data further a role for decreased indirect basal ganglia pathway activation in repetitive behavior and suggest that targeting these receptors and/or heteromeric complexes on the indirect pathway neurons of the striatum may offer pharmacotherapeutic benefit for individuals with repetitive behavior disorders.

The development of repetitive motor behaviors in deer mice: Effects of environmental enrichment, repeated testing, and differential mediation by indirect basal ganglia pathway activation.

Little is known about the mechanisms mediating the development of repetitive behaviors in human or animals. Deer mice reared with environmental enrichment (EE) exhibit fewer repetitive behaviors and greater indirect basal ganglia pathway activation as adults than those reared in standard cages. The developmental progression of these behavioral and neural circuitry changes has not been characterized. We assessed the development of repetitive behavior in deer mice using both a longitudinal and cohort design. Repeated testing negated the expected effect of EE, but cohort analyses showed that progression of repetitive behavior was arrested after 1 week of EE and differed significantly from controls after 3 weeks. Moreover, EE reductions in repetitive behavior were associated with increasing activation of indirect pathway nuclei in males across adolescence, but not females. These findings provide the first assessment of developmental trajectories within EE and support indirect pathway mediation of repetitive behavior in male deer mice.

Repetitive motor behavior: further characterization of development and temporal dynamics.

Repetitive behaviors are diagnostic for autism spectrum disorders, common in related neurodevelopmental disorders, and normative in typical development. In order to identify factors that mediate repetitive behavior development, it is necessary to characterize the expression of these behaviors from an early age. Extending previous findings, we characterized further the ontogeny of stereotyped motor behavior both in terms of frequency and temporal organization in deer mice. A three group trajectory model provided a good fit to the frequencies of stereotyped behavior across eight developmental time points. Group based trajectory analysis using a measure of temporal organization of stereotyped behavior also resulted in a three group solution. Additionally, as the frequency of stereotyped behavior increased with age, the temporal distribution of stereotyped responses became increasingly regular or organized indicating a strong association between these measures. Classification tree and principal components analysis showed that accurate classification of trajectory group could be done with fewer observations. This ability to identify trajectory group membership earlier in development allows for examination of a wide range of variables, both experiential and biological, to determine their impact on altering the expected trajectory of repetitive behavior across development. Such studies would have important implications for treatment efforts in neurodevelopmental disorders such as autism.

Repetitive Behavior in Neurodevelopmental Disorders: Clinical and Translational Findings.

Repetitive behavior refers to a highly heterogeneous set of responses associated with a wide range of conditions, including normative development. Treatment studies for aberrant repetitive behavior are limited although one promising approach involves conceptualizing such behavior as a generalized inflexibility or lack of variability in responding. Relatively little is known about the neurobiological mechanisms that mediate the development and expression of repetitive behavior, information critical to the design of effective pharmacotherapies, early interventions, and prevention strategies. We will review clinical findings in repetitive behavior as well as findings from animal models highlighting environmental factors and the role of cortical-basal ganglia circuitry in mediating the development and expression of these behaviors. Findings from animal models have included identification of a specific neural pathway important in mediating repetitive behavior. Moreover, pharmacological studies that support the importance of this pathway have led to the identification of novel potential therapeutic targets. Expanding the evidence base for environmental enrichment-derived interventions and focusing on generalized variability in responding will aid in addressing the broader problem of rigidity or inflexibility.

Environmental enrichment reduces restricted repetitive behavior by altering gray matter microstructure.

Restricted, repetitive behaviors are common symptoms in neurodevelopmental disorders including autism spectrum disorder. Despite being associated with poor developmental outcomes, repetitive behaviors remain poorly understood and have limited treatment options. Environmental enrichment attenuates the development of repetitive behaviors, but the exact mechanisms remain obscure. Using the C58 mouse model of repetitive behavior, we performed diffusion tensor imaging to examine microstructural alterations associated with the development of repetitive behavior and its attenuation by environmental enrichment. The C57BL/6 mouse strain, which displays little or no repetitive behavior, was used as a control group. We observed widespread differences in diffusion metrics between C58 mice and C57BL/6 mice. In juvenile C58 mice, repetitive motor behavior displayed strong negative correlations with fractional anisotropy in multiple gray matter regions, whereas in young adult C58 mice, high repetitive motor behavior was most strongly associated with lower fractional anisotropy and higher radial diffusivity in the striatum. Environmental enrichment increased fractional anisotropy and axial diffusivity throughout gray matter regions in the brains of juvenile C58 mice and overlapped predominantly with cerebellar and sensory regions associated with repetitive behavior. Our results suggest environmental enrichment reduces repetitive behavior development by altering gray matter microstructure in the cerebellum, medial entorhinal cortex, and sensory processing regions in juvenile C58 mice. Under standard laboratory conditions, early pathology in these regions appears to contribute to later striatal and white matter dysfunction in adult C58 mice. Future studies should examine the role these regions play in the development of repetitive behavior and the relationship between sensory processing and cerebellar deficits and repetitive behavior.

Cortico-basal ganglia white matter microstructure is linked to restricted repetitive behavior in autism spectrum disorder.

BACKGROUND: Restricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB. METHODS: We utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB. RESULTS: Individuals with ASD had significantly lower free-water corrected fractional anisotropy (FAT) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FAT and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes. LIMITATIONS: The basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated. CONCLUSIONS: These new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FAT was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB.

Reduction of restricted repetitive behavior by environmental enrichment: Potential neurobiological mechanisms.

Restricted repetitive behaviors (RRB) are one of two diagnostic criteria for autism spectrum disorder and common in other neurodevelopmental and psychiatric disorders. The term restricted repetitive behavior refers to a wide variety of inflexible patterns of behavior including stereotypy, self-injury, restricted interests, insistence on sameness, and ritualistic and compulsive behavior. However, despite their prevalence in clinical populations, their underlying causes remain poorly understood hampering the development of effective treatments. Intriguingly, numerous animal studies have demonstrated that these behaviors are reduced by rearing in enriched environments (EE). Understanding the processes responsible for the attenuation of repetitive behaviors by EE should offer insights into potential therapeutic approaches, as well as shed light on the underlying neurobiology of repetitive behaviors. This review summarizes the current knowledge of the relationship between EE and RRB and discusses potential mechanisms for EE's attenuation of RRB based on the broader EE literature. Existing gaps in the literature and future directions are also discussed.

Atypical neural processing during the execution of complex sensorimotor behavior in autism.

Stereotyped behavior is rhythmic, repetitive movement that is essentially invariant in form. Stereotypy is common in several clinical disorders, such as autism spectrum disorders (ASD), where it is considered maladaptive. However, it also occurs early in typical development (TD) where it is hypothesized to serve as the foundation on which complex, adaptive motor behavior develops. This transition from stereotyped to complex movement in TD is thought to be supported by sensorimotor integration. Stereotypy in clinical disorders may persist due to deficits in sensorimotor integration. The present study assessed whether differences in sensorimotor processing may limit the expression of complex motor behavior in individuals with ASD and contribute to the clinical stereotypy observed in this population. Adult participants with ASD and TD performed a computer-based stimulus-tracking task in the presence and absence of visual feedback. Electroencephalography was recorded during the task. Groups were compared on motor performance (root mean square error), motor complexity (sample entropy), and neural complexity (multiscale sample entropy of the electroencephalography signal) in the presence and absence of visual feedback. No group differences were found for motor performance or motor complexity. The ASD group demonstrated greater neural complexity and greater differences between feedback conditions than TD individuals, specifically in signals relevant to sensorimotor processing. Motor performance and motor complexity correlated with clinical stereotypy in the ASD group. These findings support the hypothesis that individuals with ASD have differences in sensorimotor processing when executing complex motor behavior and that stereotypy is associated with low motor complexity.

Development and temporal organization of repetitive behavior in an animal model.

Despite repetitive behaviors being a common feature of a number of clinical disorders and ubiquitous in normative development, little attention has been given to their ontogeny or temporal dynamics. We characterized these features in a mouse model of repetitive behavior to identify discrete trajectories of development and developmental changes in temporal dynamics. Three qualitatively distinct trajectory groups were identified which allowed for an examination of the interaction between temporal organization and developmental trajectory. Significant differences in temporal dynamics were found across development and among trajectory groups. Significant interactions of trajectory group and developmental period on temporal organization were also found. The combination of group-based trajectory modeling and a novel method for analysis and graphic depiction of temporal organization allowed for the exploration of the interplay between these two fundamental behavioral processes. Such methods may be useful tools in the assessment and treatment of repetitive behavior in clinical populations.

Volumetric magnetic resonance and diffusion tensor imaging of C58/J mice: neural correlates of repetitive behavior.

Restricted, repetitive behavior (RRB) involves sequences of responding with little variability and no obvious function. RRB is diagnostic for autism spectrum disorder (ASD) and a significant feature in several neurodevelopmental disorders. Despite its clinical importance, relatively little is known about how RRB is mediated by broader neural circuits. In this study, we employed ultra-high field (17.6 Tesla) magnetic resonance imaging (MRI) to study the C58/J mouse model of RRB. We determined alterations in brain morphology and connectivity of C58/J mice and their relationship to repetitive motor behavior using structural MRI and diffusion tensor imaging (DTI). Compared to the genetically similar C57BL/6 control mouse strain, C58/J mice showed evidence of structural alterations in basal ganglia and cerebellar networks. In particular, C58/J mice exhibited reduced volumes of key cortical and basal ganglia regions that have been implicated in repetitive behavior, including motor cortex, striatum, globus pallidus, and subthalamic nucleus, as well as volume differences in the cerebellum. Moreover, DTI revealed differences in fractional anisotropy and axial diffusivity in cerebellar white matter of C58/J mice. Importantly, we found that RRB exhibited by C58/J mice was correlated with volume of the striatum, subthalamic nucleus, and crus II of the cerebellum. These regions are key nodes in circuits connecting the basal ganglia and cerebellum and our findings implicate their role in RRB, particularly the indirect pathway.

Pharmacological targeting of striatal indirect pathway neurons improves subthalamic nucleus dysfunction and reduces repetitive behaviors in C58 mice.

Repetitive behaviors (e.g., stereotypic movements, compulsions, rituals) are common features of a number of neurodevelopmental disorders. Clinical and animal model studies point to the importance of cortical-basal ganglia circuitry in the mediation of repetitive behaviors. In the current study, we tested whether a drug cocktail (dopamine D2 receptor antagonist + adenosine A2A receptor agonist + glutamate mGlu5 positive allosteric modulator) designed to activate the indirect basal ganglia pathway would reduce repetitive behavior in C58 mice after both acute and sub-chronic administration. In addition, we hypothesized that sub-chronic administration (i.e. 7 days of twice-daily injections) would increase the functional activation of the subthalamic nucleus (STN), a key node of the indirect pathway. Functional activation of STN was indexed by dendritic spine density, analysis of GABA, glutamate, and synaptic plasticity genes, and cytochrome oxidase activity. The drug cocktail used significantly reduced repetitive motor behavior in C58 mice after one night as well as seven nights of twice-nightly injections. These effects did not reflect generalized motor behavior suppression as non-repetitive motor behaviors such as grooming, digging and eating were not reduced relative to vehicle. Sub-chronic drug treatment targeting striatopallidal neurons resulted in significant changes in the STN, including a four-fold increase in brain-derived neurotrophic factor (BDNF) mRNA expression as well as a significant increase in dendritic spine density. The present findings are consistent with, and extend, our prior work linking decreased functioning of the indirect basal ganglia pathway to expression of repetitive motor behavior in C58 mice and suggest novel therapeutic targets.

Differential consequences of habitual responding in a mouse model of repetitive behavior.

Restricted, repetitive behavior (RRB) is diagnostic for autism spectrum disorder (ASD) and characteristic of a number of neurodevelopmental, psychiatric, and neurological disorders. RRB seen in ASD includes repetitive motor behavior and behaviors reflecting resistance to change and insistence on sameness. C58 mice provide a robust model of repetitive motor behavior and have shown resistance to change in a reversal learning task. We further characterized resistance to change in this model by inducing habitual responding and testing for differences in the ability to suppress habitual behavior and shift to goal-directed responding. We found no differences between C58 and control (C57BL/6) mice in the acquisition of operant tasks, habit formation, and expression of habitual responding. Habitual responding, however, induced significant reversal learning and contingency reversal performance deficits in C58 mice compared with C57BL/6 mice. Decreased dendritic spine density of the dorsomedial striatum in C58 mice was related to higher repetitive motor behavior, whereas dendritic spine density in the subthalamic nucleus was significantly positively correlated with improved contingency reversal performance in both C58 and C57BL/6 mice. Our results demonstrate that induction of habitual responding markedly impaired the ability of C58 mice to shift to goal-directed behavior. Such impairment may have resulted from the effects of the induction of habitual responding on already compromised basal ganglia circuitry mediating repetitive motor behavior. These findings provide additional evidence for the translational value of the C58 model in modeling RRB in neurodevelopmental disorders. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Reduction of repetitive behavior by co-administration of adenosine receptor agonists in C58 mice.

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.

Visual feedback during motor performance is associated with increased complexity and adaptability of motor and neural output.

Complex motor behavior is believed to be dependent on sensorimotor integration - the neural process of using sensory input to plan, guide, and correct movements. Previous studies have shown that the complexity of motor output is low when sensory feedback is withheld during precision motor tasks. However, much of this research has focused on motor behavior rather than neural processing, and therefore, has not specifically assessed the role of sensorimotor neural functioning in the execution of complex motor behavior. The present study uses a stimulus-tracking task with simultaneous electroencephalography (EEG) recording to assess the effect of visual feedback on motor performance, motor complexity, and sensorimotor neural processing in healthy adults. The complexity of the EEG signal was analyzed to capture the information content in frequency bands (alpha and beta) and scalp regions (central, parietal, and occipital) that are associated with sensorimotor processing. Consistent with previous literature, motor performance and its complexity were higher when visual feedback was provided relative to when it was withheld. The complexity of the neural signal was also higher when visual feedback was provided. This was most robust at frequency bands (alpha and beta) and scalp regions (parietal and occipital) associated with sensorimotor processing. The findings show that visual feedback increases the information available to the brain when generating complex, adaptive motor output.

Procedural learning and cognitive flexibility in a mouse model of restricted, repetitive behaviour.

Restricted, repetitive behaviours (e.g., stereotypies, compulsions, rituals) in neurodevelopmental disorders have been linked to alterations in cortico-basal ganglia circuitry. Cognitive processes mediated by this circuitry (e.g., procedural learning, executive function) are likely to be impaired in individuals exhibiting high rates of repetitive behaviour. To test this hypothesis, we assessed both procedural learning and cognitive flexibility (reversal learning) using a T-maze task in deer mice (Peromyscus maniculatus) exhibiting various rates of repetitive behaviour (vertical jumping and backward somersaulting). These mice exhibited high rates of stereotypy when reared in standard rodent cages, and such behaviour was significantly attenuated by housing them in larger more complex environments. Mice reared in complex environments exhibited significantly better procedural and reversal learning than standard caged mice. Thus, early experience associated with the prevention and attenuation of stereotypy was associated with better striatally mediated learning and cognitive flexibility. Stereotypy score was significantly correlated with the number of errors made in reversal learning, and interacted with housing condition to affect overall cognitive performance. Our findings support the applicability of the deer mouse model of spontaneous stereotypy to a wider range of restricted, repetitive behaviour (e.g., insistence on sameness) typical of neurodevelopmental disorders.

Animal models of restricted repetitive behavior in autism.

Restricted, repetitive behavior, along with deficits in social reciprocity and communication, is diagnostic of autism. Animal models relevant to this domain generally fall into three classes: repetitive behavior associated with targeted insults to the CNS; repetitive behavior induced by pharmacological agents; and repetitive behavior associated with restricted environments and experience. The extant literature provides potential models of the repetitive behavioral phenotype in autism rather than attempts to model the etiology or pathophysiology of restricted, repetitive behavior, as these are poorly understood. This review focuses on our work with deer mice which exhibit repetitive behaviors associated with environmental restriction. Repetitive behaviors are the most common category of abnormal behavior observed in confined animals and larger, more complex environments substantially reduce the development and expression of such behavior. Studies with this model, including environmental enrichment effects, suggest alterations in cortical-basal ganglia circuitry in the development and expression of repetitive behavior. Considerably more work needs to be done in this area, particularly in modeling the development of aberrant repetitive behavior. As mutant mouse models continue to proliferate, there should be a number of promising genetic models to pursue.

D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder.

Obsessive-compulsive disorder is a common, chronic, and oftentimes disabling disorder. The only established first-line treatments for obsessive-compulsive disorder are exposure and response prevention therapy and the serotonin reuptake inhibitors. Many patients do not experience complete symptom resolution with either modality and require augmentation approaches. Recent animal and clinical data suggest that D-cycloserine, a partial agonist that acts at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate receptor complex, may enhance extinction learning that occurs in exposure-based psychotherapies. Given this, this study examined if D-cycloserine (250 mg) enhances the overall efficacy and rate of change of exposure and response prevention therapy for adult obsessive-compulsive disorder. Participants were 24 adults meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for obsessive-compulsive disorder. The study design was a randomized, double-blinded, placebo-controlled augmentation trial examining exposure and response prevention therapy+D-cycloserine versus exposure and response prevention therapy+placebo. All patients received 12 weekly sessions of exposure and response prevention treatment. The first session involved building a ritual hierarchy and providing psychoeducation about obsessive-compulsive disorder. The second session involved a practice exposure. Sessions 3-12 involved exposure and response prevention exercises. D-cycloserine or placebo (250 mg) was taken 4 h before every session. No significant group differences were found across outcome variables. The rate of improvement did not differ between groups. The present results fail to support the use of D-cycloserine with exposure and response prevention therapy for adult obsessive-compulsive disorder. As this study is the first to explore this question and a number of methodological issues must be considered when interpreting the findings, the conclusions that may be drawn from our results are limited.

A Cohesive Framework for Motor Stereotypy in Typical and Atypical Development: The Role of Sensorimotor Integration.

Stereotyped motor behavior manifests as rhythmic, repetitive movements. It is common in several neurologic and psychiatric disorders where it is considered maladaptive. However, it also occurs early in typical development where it serves an adaptive function in the development of complex, controlled motor behavior. Currently, no framework accounts for both adaptive and maladaptive forms of motor stereotypy. We propose a conceptual model that implicates sensorimotor mechanisms in the phenomenology of adaptive and maladaptive stereotypy. The extensive structural and functional connectivity between sensory and motor neural circuits evidences the importance of sensory integration in the production of controlled movement. In support of our model, motor stereotypy in normative development occurs when the sensory and motor brain regions are immature and the infant has limited sensory and motor experience. With maturation and experience, complex movements develop and replace simple, stereotyped movements. This developmental increase in motor complexity depends on the availability of sensory feedback indicating that the integration of sensory information with ongoing movement allows individuals to adaptively cater their movements to the environmental context. In atypical development, altered neural function of sensorimotor circuitry may limit an individual's ability to integrate sensory feedback to adapt movements to appropriately respond to environmental conditions. Consequently, the motor repertoire would remain relatively simple, resulting in the persistence of motor stereotypy. A framework that considers motor stereotypy as a manifestation of low motor complexity resulting from poor sensorimotor integration has many implications for research, identification and treatment of motor stereotypy in a variety of developmental disorders.